Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors

被引：36

作者：

Bungard, Christopher J. ^{[1
]}

Williams, Peter D. ^{[1
]}

Schulz, Jurgen ^{[1
]}

Wiscount, Catherine M. ^{[1
]}

Holloway, M. Katharine ^{[1
]}

Loughran, H. Marie ^{[1
]}

Manikowski, Jesse J. ^{[1
]}

Su, Hua-Poo ^{[1
]}

Bennett, David J. ^{[1
]}

Chang, Lehua ^{[2
]}

Chu, Xin-Jie ^{[2
]}

Crespo, Alejandro ^{[2
]}

Dwyer, Michael P. ^{[2
]}

Keertikar, Kartik ^{[2
]}

Morriello, Gregori J. ^{[2
]}

Stamford, Andrew W. ^{[2
]}

Waddell, Sherman T. ^{[2
]}

Zhong, Bin ^{[3
]}

Hu, Bin ^{[3
]}

Jo, Tao ^{[3
]}

Diamond, Tracy L. ^{[1
]}

Bahnck-Teets, Carolyn ^{[1
]}

Carroll, Steven S. ^{[1
]}

Fay, John F. ^{[1
]}

Min, Xu ^{[1
]}

Morris, William ^{[2
]}

Ballard, Jeanine E. ^{[1
]}

Miller, Michael D. ^{[1
]}

McCauley, John A. ^{[1
]}

机构：

[1] Merck & Co Inc, 770 Sumneytown Pike,POB 4, West Point, PA 19486 USA

[2] Merck & Co Inc, 126 East Lincoln Ave, Rahway, NJ 07065 USA

[3] WuXi AppTec, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 12期

关键词：

HIV-1 protease inhibitors; MK-8718; FL-100; piperazine sulfonamide; ALDEHYDES;

D O I：

10.1021/acsmedchemlett.7b00386

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

引用

页码：1292 / 1297

页数：6

共 17 条

[1] Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group [J].

Bungard, Christopher J. ;

Williams, Peter D. ;

Ballard, Jeanine E. ;

Bennett, David J. ;

Beaulieu, Christian ;

Bahnck-Teets, Carolyn ;

Carroll, Steve S. ;

Chang, Ronald K. ;

Dubost, David C. ;

Fay, John F. ;

Diamond, Tracy L. ;

Greshock, Thomas J. ;

Hao, Li ;

Holloway, M. Katharine ;

Felock, Peter J. ;

Gesell, Jennifer J. ;

Su, Hua-Poo ;

Manikowski, Jesse J. ;

McKay, Daniel J. ;

Miller, Mike ;

Min, Xu ;

Molinaro, Carmela ;

Moradei, Oscar M. ;

Nantermet, Philippe G. ;

Nadeau, Christian ;

Sanchez, Rosa I. ;

Satyanarayana, Tummanapalli ;

Shipe, William D. ;

Singh, Sanjay K. ;

Vouy Linh Truong ;

Vijayasaradhi, Sivalenka ;

Wiscount, Catherine M. ;

Vacca, Joseph P. ;

Crane, Sheldon N. ;

McCauley, John A. .

ACS MEDICINAL CHEMISTRY LETTERS, 2016, 7 (07) :702-707

[2]

Carmosin R J., Preparation of octahydropyrrolo-[3,4-c]carbazoles useful as analgesic agents, Patent No. [W09965911A1, 9965911A1]

[3]

COREY EJ, 1972, TETRAHEDRON LETT, P3769

[4] Expedite Protocol for Construction of Chiral Regioselectively N-Protected Monosubstituted Piperazine, 1,4-Diazepane, and 1,4-Diazocane Building Blocks [J].

Crestey, Francois ;

Witt, Matthias ;

Jaroszewski, Jerzy W. ;

Franzyk, Henrik .

JOURNAL OF ORGANIC CHEMISTRY, 2009, 74 (15) :5652-5655

[5] PL-100, a Novel HIV-1 Protease Inhibitor Displaying a High Genetic Barrier to Resistance: An In Vitro Selection Study [J].

Dandache, Serge ;

Coburn, Craig A. ;

Oliveira, Maureen ;

Allison, Timothy J. ;

Holloway, M. Katharine ;

Wu, Jinzi J. ;

Stranix, Brent R. ;

Panchal, Chandra ;

Wainberg, Mark A. ;

Vacca, Joseph P. .

JOURNAL OF MEDICAL VIROLOGY, 2008, 80 (12) :2053-2063

[6] READILY ACCESSIBLE 12-I-5 OXIDANT FOR THE CONVERSION OF PRIMARY AND SECONDARY ALCOHOLS TO ALDEHYDES AND KETONES [J].

DESS, DB ;

MARTIN, JC .

JOURNAL OF ORGANIC CHEMISTRY, 1983, 48 (22) :4155-4156

[7] CLEAVAGE OF HIV-1 GAG POLYPROTEIN SYNTHESIZED INVITRO - SEQUENTIAL CLEAVAGE BY THE VIRAL PROTEASE [J].

ERICKSONVIITANEN, S ;

MANFREDI, J ;

VIITANEN, P ;

TRIBE, DE ;

TRITCH, R ;

HUTCHISON, CA ;

LOEB, DD ;

SWANSTROM, R .

AIDS RESEARCH AND HUMAN RETROVIRUSES, 1989, 5 (06) :577-591

[8] Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS [J].

Ghosh, Arun K. ;

Osswald, Heather L. ;

Prato, Gary .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (11) :5172-5208

[9] STRUCTURE AT 2.5-A RESOLUTION OF CHEMICALLY SYNTHESIZED HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE COMPLEXED WITH A HYDROXYETHYLENE-BASED INHIBITOR [J].

JASKOLSKI, M ;

TOMASSELLI, AG ;

SAWYER, TK ;

STAPLES, DG ;

HEINRIKSON, RL ;

SCHNEIDER, J ;

KENT, SBH ;

WLODAWER, A .

BIOCHEMISTRY, 1991, 30 (06) :1600-1609

[10] ACTIVE HUMAN IMMUNODEFICIENCY VIRUS PROTEASE IS REQUIRED FOR VIRAL INFECTIVITY [J].

KOHL, NE ;

EMINI, EA ;

SCHLEIF, WA ;

DAVIS, LJ ;

HEIMBACH, JC ;

DIXON, RAF ;

SCOLNICK, EM ;

SIGAL, IS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (13) :4686-4690

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